1. Field of the Invention
The present invention relates to a method for the preparation of N-[1(R)-(1-naphthyl)ethyl]-N-[3-[3-(trifluoromethyl)phenyl]propyl]-1-amine, Cinacalcet, and to new intermediates and impurities formed during the preparation.
2. Background of the Invention
N-[1(R)-(1-naphthyl)ethyl]-N-[3-[3-(trifluoromethyl)phenyl]propyl]-1-amine (herein “Cinacalcet” or “CNC”) has a CAS number of 226256-56-0, a formula of C22H22F3N and the following structure:

This molecule is the free base form of Cinacalcet hydrochloride (herein “CNC-HCl”), having a CAS number of 364782-34-3 and the following structure:

CNC-HCl is marketed as SENSIPAR™, and is the first drug in a class of compounds known as calcimimetics to be approved by the FDA.
Calcimimetics are a class of orally active, small molecules that decrease the secretion of PTH by activating calcium receptors. The secretion of PTH is normally regulated by the calcium-sensing receptor. Calcimimetic agents increase the sensitivity of this receptor to calcium, which inhibits the release of parathyroid hormone, and lowers parathyroid hormone levels within a few hours. Calcimimetics are used to treat hyperparathyroidism, a condition characterized by the oversecretion of PTH that results when calcium receptors on parathyroid glands fail to respond properly to calcium in the bloodstream. Elevated levels of parathyroid hormone (PTH), an indicator of secondary hyperparathyroidism, are associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk for cardiovascular death. As a calcimimetic, CNC-HCl is approved for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Treatment with CNC-HCl lowers serum levels of PTH, as well as the calcium/phosphorus ion product in the blood.
U.S. Pat. No. 6,211,244 discloses calcium receptor-active compounds related to Cinacalcet and methods of making such compounds. In accordance with the patent, Cinacalcet may be produced by reacting 1-acetyl naphthalene with 3-[3-(trifluoromethyl)phenyl]propylamine in the presence of titanium isopropoxide to produce an imine corresponding to Cinacalcet, followed by treatment with methanolic sodium cyanoborohydride and resolution of the racemic Cinacalcet base by chiral liquid chromatography, according to Scheme 1:

Similarly, using the process disclosed in U.S. Pat. No. 6,211,244, as well as DRUGS OF THE FUTURE (2002) 27 (9): 831 the desired Cinacalcet enantiomer may be produced by reacting (R)-1-(1-naphthyl)ethylamine with 3-[3-(trifluoromethyl)phenyl]propionaldehyde in the presence of titanium isopropoxide to produce the imine that corresponds to Cinacalcet, followed by treatment with ethanolic sodium cyanoborohydride, according to the following Scheme 2:

U.S. Pat. No. 6,211,244 discloses an additional process for the synthesis of Cinacalcet. This process involves treating 3-trifluoromethylcinnamonitrile, which can be prepared as disclosed in U.S. Pat. No. 4,966,988, with diisobutyl aluminum hydride, followed by treating the intermediate aluminumimine complex with (R)-1-(1-naphthyl)ethylamine, and reducing the intermediate imine with ethanolic sodium cyanoborohydride, according to the following Scheme 3:

These three processes however, require the use of reagents such as titanium isopropoxide, which is highly hygroscopic and expensive, as well as toxic, and ethanolic or methanolic sodium cyanoborohydride, which is highly toxic and flammable, and not environmentally friendly, making the processes difficult to apply on industrial scale. The chiral separation method used in Scheme 1 to obtain the desired enantiomer is industrially not feasible and economically not viable. Further, losing half molecule after its complete formation is industrially, particularly economically, not viable.
Additionally, the product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. Like any synthetic compound, Cinacalcet can contain related substances or impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products.
Generally, impurities are indentified spectroscopically and/or with another physical method, and then are associated with a peak position, such as that in a chromatogram, or with a spot on a TLC plate. Thereafter, the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is measure in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the “retention time.”
Retention time can vary about a mean value based upon the condition of the instrumentation as well as many other factors. To mitigate the effects such variations have upon accurate identification of an impurity, those skilled in the art use the “relative retention time” (RRT) to identify impurities. The RRT of an impurity is its retention time divided by the retention time of a reference marker.
One skilled in the art understands that a compound in a relatively pure state can be used as a “reference standard.” The reference standard is similar to the reference marker, which is used for qualitative analysis only, but is used to quantify the amount of the compound of the reference standard in an unknown mixture as well. A reference standard is an “external standard,” when a solution of a known concentration of the reference standard and an unknown mixture are analyzed using the same technique. The amount of the compound in the mixture can be determined by comparing the magnitude of the detector response.
The reference standard can also be used to quantify the amount of another compound in the mixture if a “response factor,” which compensates for differences in the sensitivity of the detector to the two compounds, has been predetermined. For this purpose, the reference standard is added directly to the mixture, and is known as an “internal standard.”
The management of process related impurities is enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.
Thus, an alternative process for the preparation of Cinacalcet base and Cinacalcet salt, which is direct, environmentally friendly, applicable to industrial scale production, and leading to higher yield, is desirable. Additionally, it is desirable that there is a method for identifying, quantifying and separating the impurities formed as a result of the synthesis of Cinacalcet.